BACKGROUND: Ischemia/reperfusion injury (IRI) presents a significant hurdle in lung transplantation. Our previous research showed that the glucagon-like peptide-1 receptor (GLP-1R) agonist liraglutide (Lir) improves lipopolysaccharide-induced acute lung injury in murine models. This study aims to further investigate the lung-protective mechanisms of GLP-1R agonist. METHODS: An in vitro hypoxia/reoxygenation (H/R) model with BEAS-2B cells and an in vivo donation after cardiac death (DCD) rat lung transplant model were utilized. Lir was administered using an ex vivo lung perfusion (EVLP) system. Lung function, injury, and pyroptosis mechanisms were assessed. Validation experiments included quantitative reverse transcription PCR, immunoblot analysis, activity assays and proteomic analysis, among others, to evaluate how GLP-1R agonist protect lungs from IRI by modulating pyroptosis, thereby improving lung function and reducing injury. RESULTS: Perfusion of the donor lung with Lir using EVLP improved the function of DCD lungs and mitigated IRI. Bioinformatics analysis and validation experiments provided evidence of increased expression of NOD-like receptors signals and pyroptosis in lung transplantation IRI, which was suppressed by Lir treatment. Further investigations revealed that the thioredoxin-binding protein (TXNIP) played a crucial regulatory role in the pyroptosis of IRI, with the NOD-like receptor family pyrin domain-containing 3 (NLRP3) emerging as a key target. In addition, this study found that Lir promotes GLP-1R-dependent TXNIP ubiquitination and modulates TXNIP mRNA stability via the GLP-1R/miR-17 axis. CONCLUSION: This study demonstrates, for the first time, that a novel EVLP-based drug delivery approach using GLP-1R agonist can protect lungs from IRI by modulating pyroptosis, thereby improving lung function and reducing injury. The research uncovers a previously unknown mechanism where GLP-1R agonist modulates the protein TXNIP through GLP-1R/miR-17 signaling. These insights underscore the potential of GLP-1R agonists as targeted therapies for primary graft dysfunction in lung transplant recipients, opening new avenues for clinical interventions to improve transplant outcomes.